Method for treating severe heart failure and medicament therefor

ABSTRACT

A method for treating severe heart failure, comprising administering to a patient an effective amount of a benzazepine compound (1): wherein R 1  is H or halogen, R 2  is OH, or —NR 5 R 6  (R 5  and R 6  are H or lower alkyl, R 3  is H, halogen, lower alkyl, or lower alkoxy, R 4  is halogen, lower alkyl or lower alkoxy, or a salt thereof, and a pharmaceutical composition containing the benzazepine compound (1) or a salt thereof and use of the compound (1) or a salt thereof for preparing a medicament for treatment of severe heart failure

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Phase application based onPCT/JP2004/002085, filed on Feb. 23, 2004, the contents of which areincorporated herein by reference and claims the benefit of U.S.Provisional Application No. 60/448,878, filed on Feb. 24, 2003, thecontents of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a method for treating severe heartfailure with a medicament comprising as an active ingredient abenzazepine compound, and a medicament useful therefor. Moreparticularly, the present invention relates to a method for treatingsever heart failure comprising administering to a patient in needthereof a therapeutically effective amount of a benzazepine compound ofthe formula (1):

wherein R¹ is a hydrogen atom or a halogen atom, R² is a hydroxy group,or a group of the formula: —NR⁵R⁶ wherein R⁵ and R⁶ are the same ordifferent and are each a hydrogen atom or a lower alkyl group, R³ is ahydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxygroup, R⁴ is a halogen atom, a lower alkyl group or a lower alkoxygroup, or a pharmaceutically acceptable salt thereof.

The present invention provides further a medicament for the treatment ofthe severe heat failure comprising as an active ingredient the abovebenzazepine compound (1) as well as use of the above benzazepinecompound (1) for the preparation of a medicament useful for thetreatment of severe heart failure.

BACKGROUND ART

It is known that the benzazepine compounds of the formula (1) havevasopressin antagonistic activity and are useful as a vasodilator,hypotensive agent, diuretic agent, platelet aggregation inhibitor, etc.(cf. WO 91/05549, U.S. Pat. Nos. 5,258,510, 5,753,677, JP-A-6-80641) andfurther that those compounds are also useful as an oxytocin antagonist(WO 94/01113), a cataract treating agent (WO 94/18975, U.S. Pat. No.5,827,862), a cerebral edema treating agent (JP-A-8-157368), a Meniere'sdisease treating agent (JP-A-10-120592), or an antiulcer agent(JP-A-7-188021).

Despite significant advances in the prevention and treatment ofcardiovascular disease in the United States over the past two decades,as reflected by a 50% reduction in age-specific mortality from coronaryartery disease (CAD) (American Heart Association, Heart and Strokefacts: 1996 statistical supplement, Page 15), the prevalence of heartfailure has been steadily increasing (Massie B M, Shah N B, The heartfailure epidemic, Curr. Opin. Cardiol. 1996, 11:221-226). This is mostlikely a result of the aging of the US population and the greaterlongevity of CAD patients. Approximately five million individualscurrently have chronic congestive heart failure, and it has beenestimated that 400,000 new cases of heart failure are diagnosed eachyear (Massie B M, Shah N B, The heart failure epidemic, Curr. Opin.Cardiol. 1996, 11:221-226). And approximately 20% of the patients needto be hospitalized each year for worsening of the disease state(“Cardium”, published by Decision Resources (1998)). It has been shownthat approximately 50% of patients with heart failure die within 5 yearsof their diagnosis (Konstam M, Dracut K, Baker D, et al., Heart failure:evaluation and care of patients with left ventricular dysfunction, AHCRPPublication No. 94-0612, Rockville (Md.): US Department of Health andHuman Service; June 1994).

In the United States, the cost of treating heart failure has beenestimated to be in excess of $12 billion annually and as high as $30billion, excluding costs related to lost wages and productivity (LevitzK R, Lazenby H C, Cown C A, et al., National health expenditures, 1990,Health Care Fin Rev 1991, 13:29-54; O'Connell J B, Bristow M R, Economicimpact of heart failure in the United States: time for a differentapproach, J Heart Lung Transplant 1994, 13:107-12). The cost ofhospitalization alone exceeds $7 billion (O'Connell J B, Bristow M R,Economic impact of heart failure in the United States: time for adifferent approach, J Heart Lung Transplant 1994, 13:107-12).

Heart failure can be defined as a complex clinical syndromecharacterized by abnormalities of left ventricular function andneurohormonal regulation, which in turn can result in effortintolerance, fluid retention, and reduced longevity.

The heart failure is classified to “acute heart failure” and “chronicheart failure” or “chronic heart failure in acute exacerbation” based onthe clinical symptoms and the disease course.

The therapeutic measures for heart failure are entirely differentdepending on the conditions, i.e., whether it is in the chronic phase orin the acute phase. For the treatment of the chronic heart failure, itis treated so as to release the remaining heart failure symptom and tomaintain in the stable state so that the symptom does not fall intochronic heart failure in acute exacerbation. On the other hand, when thepatient falls into chronic heart failure in acute exacerbation, thesymptom may possibly change rapidly for the worse and there is threat tolife, and hence, from this viewpoint, it is necessary to take alife-saving measure by temporarily controlling the breath and bloodpressure and administering a cardiotonic drug so as to moderate andstabilize the clinical symptoms, in hemodynamic viewpoint, by increasingcardiac output, decreasing intravascular circulation volume, andincreasing renal blood flow.

Since most heart failures can not be treated by causal therapy, thesymptoms change gradually for the worse with the lapse of time. Eventhough the cardiac function is temporarily recovered by a temporarysymptomatic therapy, the function changes for the worse later and it isimpossible to effect a permanent cure. The worsening rate variesdepending on various conditions such as the kinds of underline diseases,severity of the disease, effectiveness of therapy, and livingenvironment. Besides, the patients sometimes unexpectedly suddenly die,even while they have been in the favorable course of recovering. Thepatients of heart failure have bad prognosis as to the life. Accordingto the statistics by Framingham Study in the U.S.A. including the dataof all patients suffering from heart diseases, the 50% survival rate isshown in about 4 years since onset of the disease (Kannel, W B, et al.,1982, Mckee, P A, et al., 1982). Besides, in New York Heart AssociationClass, the patients suffering from the disease in the severity I of thedisease, they show good prognosis, but the patients have the severity IVof the disease show the 50% survival rate in less than 1 year, thatthose having the severity II or III of the disease show the 50% survivalrate in less than 4 years. Thus, the patients, who are diagnosed to besevere heart failure, have bad prognosis. (cf. Integrated Handbook ofInternal Medicine, Volume 30, 1990, Nakayma Shoten).

DISCLOSURE OF INVENTION

The present inventors have intensively studied for seeking a method forthe treatment of severe heart failure as well as a new medicament usefultherefor. As the result, they have found that the benzazepine compoundsof the formula (1) are effective for the treatment of severe heartfailure, and have completed the present invention.

Thus, the present invention includes the following various embodiments.

[1] In a first embodiment, the present invention provides a new methodfor the treatment of severe heart failure, which comprises administeringto a patient in need thereof a therapeutically effective amount of abenzazepine compound of the formula (1):

wherein R¹ is a hydrogen atom or a halogen atom, R² is a hydroxy group,or a group of the formula: —NR⁵R⁶ wherein R⁵ and R⁶ are the same ordifferent and are each a hydrogen atom or a lower alkyl group, R³ is ahydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxygroup, R⁴ is a halogen atom, a lower alkyl group or a lower alkoxy, or apharmaceutically acceptable salt thereof.

[2] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the active compound (1) is administered in a dose of less than0.6 mg/kg per day.

[3] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the active compound (1) is administered in a dose range from 0.1mg/kg to less than 0.6 mg/kg per day.

[4] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the active compound (1) is administered in a dose of 15 mg to 45mg/body per day.

[5] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the active compound (1) is5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[6] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the active compound (1) is5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[7] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the severe heart failure is acute heart failure or a chronicheart failure in acute exacerbation.

[8] In another embodiment, the present invention provides a method forthe treatment of severe heart failure according to the above [1],wherein the severe heart failure is a severe heart failure of New YorkHeart Association Class: III and IV.

[9] In another embodiment, the present invention provides a newmedicament for the treatment of severe heart failure which comprises asan active ingredient a benzazepine compound of the formula (1) or apharmaceutically acceptable salt thereof.

[10] In another embodiment, the present invention provides a medicamentaccording to the above [9], wherein the active compound (1) is5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[11] In another embodiment, the present invention provides a medicamentaccording to the above [9], wherein the active compound (1) is5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[12] In another embodiment, the present invention provides apharmaceutical composition suitable for the treatment of severe heartfailure which comprises as an active ingredient a benzazepine compoundof the formula (1) or a pharmaceutically acceptable salt thereof inadmixture with a conventional pharmaceutically acceptable carrier ordiluent.

[13] In another embodiment, the present invention provides apharmaceutical composition according to the above [12], wherein theactive compound (1) is5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[14] In another embodiment, the present invention provides apharmaceutical composition according to the above [12], wherein theactive compound (1) is5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[15] In another embodiment, the present invention provides apharmaceutical composition according to any one of the above [12] to[14], wherein the active compound (1) is contained in an amount of 1 to70% by weight based on the weight of the composition.

[16] In another embodiment, the present invention provides a use of abenzazepine compound of the formula (1) or a pharmaceutically acceptablesalt thereof for manufacturing a medicament suitable for the treatmentof severe heart failure.

[17] In another embodiment, the present invention provides a use of abenzazepine compound (1) or a pharmaceutically acceptable salt thereofaccording to the above [16], wherein the active compound (1) is5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[18] In another embodiment, the present invention provides a use of abenzazepine compound (1) or a pharmaceutically acceptable salt thereofaccording to the above [16], wherein the active compound (1) is5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

[19] In another embodiment, the present invention provides a use of abenzazepine compound (1) or a pharmaceutically acceptable salt thereofaccording to any one of the above [16] to [18], wherein the activecompound (1) is contained in the medicament in a daily dosage unit ofthe range of less than 0.6 mg/kg.

BEST MODE FOR CARRYING OUT THE INVENTION

The medicament suitable for the method for treating severe heart failureof the present invention comprises as an active ingredient at least oneof the benzazepine compounds of the above formula (1) or apharmaceutically acceptable salt thereof.

In the description and claims, the groups in the above formula (1)denote the following groups.

The “halogen atom” denotes a fluorine atom, a chlorine atom, a bromineatom, or an iodine atom. The “lower alkyl group” denotes a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl.

The “lower alkoxy group” denotes a straight chain or branched chainalkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.

Besides, the term “severe heart failure” in the description and claimsmeans acute heart failure and chronic heart failure in acuteexacerbation, for example, heart failures as classified in New YorkHeart Association Class: III and IV. New York Heart Association ClassIII and IV (The Criteria Committee of the New York Heart Association:Diseases of the Heart and Blood Vessels, Nomenclature and Criteria ofDiagnosis, 6th ed. P. 110, Little, Brown & Co., Boston (1964)) aredefined as follows: CLASS III. Patients with cardiac disease resultingin marked limitation of physical activity. They are comfortable at rest.Less than ordinary physical activity causes fatigue, palpitation,dyspnea, or anginal pain. CLASS IV. Patients with cardiac diseaseresulting in inability to carry on any physical activity withoutdiscomfort. Symptoms of cardiac insufficiency or of the anginal syndromemay be present even at rest. If any physical activity is undertaken,discomfort is increased.

According to the method of the present invention, the active benzazepinecompound (1) is effective in an amount much less than the dose aspreviously claimed in the existing patent (WO 91/05549). That is, thecompound (1) is used, for example, as an antiulcer drug, it is usuallyadministered in a dose range from 0.6 to 50 mg/kg per day, e.g. 60 mg to90 mg/body per day, but according to the studies by the presentinventors, it has been found that when the compound (1) was administeredin a dose range from 0.1 mg/kg to less than 0.6 mg/kg per day, andpreferably in a dose of 15 mg to 45 mg/body per day, more preferably ina dose of about 30 mg/body per day, it was effective for decreasing ofthe body weight and increasing of the urine volume without undesirableside effects such as frequent urination, etc. and then can improve edemaand mortality rate, and it has further been found that in the patientssuffering from hyponatremia, it was observed increase of sodium level inserum.

Thus, according to the method of the present invention, even in thepatients suffering from severe heart failure who have bad prognosis, theprognosis has been is significantly improved, and hence, the method ofthe present invention is useful for the treatment of severe heartfailure.

The benzazepine compounds of the formula (1) and processes for preparingthe same are disclosed in WO 91/05549, U.S. Pat. Nos. 5,258,510 and5,753,677 as well as in the Japanese counterpart JP-A-6-80641.

The benzazepine compounds of the formula (1) can readily form apharmaceutically acceptable acid addition salt with a pharmaceuticallyacceptable acid. The pharmaceutically acceptable acids include inorganicacids, such as sulfuric acid, hydrochloric acid, phosphoric acid,hydrobromic acid, etc. and organic acids such as acetic acid,p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, succinic acid,benzoic acid, etc.

Among the benzazepine compounds of the formula (1), the compounds havingan acidic group can readily form a salt with a pharmaceuticallyacceptable basic compound. The basic compounds include metal hydroxidessuch as sodium hydroxide, potassium hydroxide, lithium hydroxide,calcium hydroxide, etc.; alkali metal carbonates or hydrogen carbonates,such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate, etc.; and alkali metalalcoholates such as sodium methylate, potassium methylate, etc.

The active compounds (1) of the present invention are used in the formof a conventional pharmaceutical preparation. The preparation isprepared by using conventional diluents or carriers such as fillers,thickening agents, binders, wetting agents, disintegrators, surfactants,lubricants, and the like. The pharmaceutical preparations can beselected from various forms in accordance with the desired utilities,and the representative forms are tablets, pills, powders, solutions,suspensions, emulsions, granules, capsules, suppositories, injections(solutions, suspensions, etc.), and the like.

In order to form in tablets, there are used well known pharmaceuticalcarriers such as vehicles (e.g. lactose, white sugar, sodium chloride,glucose, urea, starch, xylitol, mannitol, erythritol, sorbitol, calciumcarbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders(e.g. water, ethanol, propanol, simple syrup, glucose solution, starchsolution, gelatin solution, carboxylmethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.),disintegrators (e.g. dry starch, sodium alginate, agar powder, laminaranpowder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylenesorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride,starches, lactose, etc.), disintegration inhibitors (e.g. white sugar,stearin, cacao butter, hydrogenated oils, etc.), absorption promoters(e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wettingagents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches,lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g.purified talc, stearates, boric acid powder, polyethylene glycol, etc.),and the like. Moreover, the tablets may also be in the form of aconventional coated tablet, such as sugar-coated tablets, gelatin-coatedtablets, enteric coated tablets, film coating tablets, or double ormultiple layer tablets. In the preparation of pills, the conventionalcarriers can be used and include, for example vehicles (e.g. glucose,lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin,talc, etc.), binders (e.g. gum arabic powder, tragacanth powder,gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.) andthe like. In the preparation of suppositories, the conventional carrierscan be used and include, for example, polyethylene glycol, cacao butter,higher alcohol, higher alcohol esters, gelatin, semi-syntheticglycerides, and the like. Capsules can be prepared by charging a mixtureof the compound of the present invention and the above carriers intohard gelatin capsules, soft capsules or hydroxypropylmethyl cellulosecapsules (HPMC capsules) in usual manner. In the preparation ofinjections, the solutions, emulsions and suspensions are sterilized andare preferably made isotonic with the blood. In the preparation of thesesolutions, emulsions and suspensions, there are used conventionaldiluents such as water, ethyl alcohol, macrogol, propylene glycol,ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,polyoxyethylene sorbitan fatty acid esters, and the like. In this case,the pharmaceutical preparations may also be incorporated with odiumchloride, glucose, or glycerin in an amount sufficient to make themisotonic, and may also be incorporated with conventional solubilizer,buffers, anesthetizing agents. Moreover, the pharmaceutical preparationsmay optionally be incorporated with coloring agents, preservatives,perfumes, flavors, sweetening agents, and other medicaments, ifrequired.

The amount of the active compound (1) to be incorporated into thepharmaceutical composition of the present invention is not specified butmay be selected from a broad range, but usually, it is preferably in therange of 1 to 70% by weight, more preferably 5 to 50% by weight, basedon the weight of the composition.

The suitable method for administration of the medicament of the presentinvention may be determined in accordance with various forms ofpreparations, ages, sexes and other conditions of the patients, thedegree of severity of diseases, and the like. For example, tablets,pills, solutions, suspensions, emulsions, granules and capsules areadministered orally. The injections are intravenously administered aloneor together with a conventional auxiliary liquid (e.g. glucose, aminoacid solutions), and further are optionally administered alone inintramuscular, intracutaneous, subcutaneous, or intraperitoneal route,if required. Suppositories are administered in intrarectal route.

The dosage of the active compound of the present invention may beselected in accordance with the usage, ages, sexes and other conditionsof the patients, the degree of severity of the diseases, and the like,but it is usually in the range of less that 0.6 mg/kg per day,preferably from 0.1 mg/kg to less than 0.6 mg/kg per day. The suitabledose is in the range of 15 mg to 45 mg/body per day.

EXAMPLES

The present invention is illustrated in more detail by the followingpreparations and experiments, but should not be construed to be limitedthereto.

Preparation 1

5-Dimethylamino-1-[4-(2-methylbenzoylamino)- 150 gbenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine Avicel (trade name,manufactured by Asahi  40 g Chemical Industry, Co., Ltd., Japan) CornStarch  30 g Magnesium stearate  2 g Hydroxypropyl methylcellulose  10 gPolyethylene glycol-6000  3 g Castor oil  40 g Ethanol  40 g

The active compound of the present invention, Avicel, corn starch andmagnesium stearate are mixed and kneaded and the mixture is tabletted byusing a conventional pounder (R 10 mm) for sugar coating. The tabletsthus obtained are coated with a film coating agent consisting ofhydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil andethanol to give film coated tablets.

Preparation 2

5-Hydroxy-7-chloro-[2-methyl-4-(2-methylbenzoylamino)-  150 gbenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine Citric acid  1.0 g Lactose33.5 g Dicalcium phosphate 70.0 g Pullonic F-68 30.0 g Sodiumlaurylsulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol(Carbowax 1500)  4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Cornstarch 30.0 g Dry sodium laurylsulfate  3.0 g Dry magnesium stearate 3.0 g Ethanol q.s.

The active compound of the present invention, citric acid, lactose,dicalcium phosphate, Pullonic F-68 and sodium laurylsulfate are mixed.

The mixture is screened with No. 60 screen and is granulated with analcohol solution containing polyvinylpyrrolidone, Carbowax 1500 andCarbowax 6000. If required, an alcohol is added thereto so that thepowder mixture is made a paste-like mass. Corn starch is added to themixture and the mixture is continuously mixed to form uniform particles.The resulting particles are passed through No. 10 screen and enteredinto a tray and then dried in an oven at 100° C. for 12 to 14 hours. Thedried particles are screened with No. 16 screen and thereto are addeddry sodium laurylsulfate and dry magnesium stearate, and the mixture istabletted to form the desired shape.

The core tablets thus prepared are varnished and dusted with talc, inorder to guard them from wetting. Undercoating is applied to the coretablets. In order to administer the tablets orally, the core tablets arevarnished several times. In order to give round shape and smooth surfaceto the tablets, further undercoating and coating with a lubricant areapplied thereto. The tablets are further coated with a coloring coatingmaterial until the desired colored tablets are obtained. After drying,the coated tablets are polished to obtain the desired tablets havinguniform gloss.

Preparation 3

5-Hydroxy-7-chloro-[2-methyl-4-(2-methylbenzoylamino)-   5 gbenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine Polyethylene glycol(molecular weight; 4000)  0.3 g Sodium chloride  0.9 g Polyoxyethylenesorbitan monooleate  0.4 g sodium metabisulfite  0.1 g Methyl paraben0.18 g Propyl paraben 0.02 g Distilled water for injection 10.0 ml

The above parabens, sodium metabisulfite and sodium chloride aredissolved in distilled water of about half volume of the above withstirring at 80° C. The solution thus obtained is cooled to 40° C., andthe active compound of the present invention and further polyethyleneglycol and polyoxyethylene sorbitan monooleate are dissolved in theabove solution. To the solution is added distilled water for injectionto adjust to the desired volume, and the solution is sterilized byfiltering with an appropriate filter paper to give an injectionpreparation.

Experiments

(1) Methods:

To patients of severe heart failure (i.e., patient in acute heartfailure or chronic heart failure in acute exacerbation, New York HeartAssociation Class III and IV) was administered5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepineat a dose of 30, 60 or 90 mg/day for a period of 60 days, which periodbegan from the duration of hospitalization to after being dischargedfrom hospital (details thereof are shown in Table 1).

(2) Results:

The results are shown in Tables 2 to 7.

As to the statistical analysis, the data in Table 2 was analyzed byANOVA method, and the data in Tables 3 and 4 were analyzed by ANCOVAmethod, and the data in Table 5 was analyzed by Log-Rank test.

When the dosages in this experiment were converted to a daily dose per 1kg of body weight, they were 0.371±0.096 mg/kg (n=77) in the 30mg-treated group, 0.769±0.205 mg/kg (n=83) in the 60 mg-treated group,and 1.149±0.283 mg/kg (n=76) in the 90 mg-treated group (all inmean±SD).

As is shown in the results, in the 30 mg-treated group, the total urineoutput was increased (Table 2), and the body weight was decreased (Table3). In addition, patients of hyponatremia at baseline (patients havingthe serum sodium concentration lower than the normal (less than 136mEq/L)) showed the increase of serum sodium concentration (Table 4).

In the same experiment, the mortality rate throughout the entire periodfrom the period of hospitalization until the termination of medicationat the outpatient department was significantly lower in the 30mg-treated group than the control group, which was analyzed with takinginto consideration of the time in days from the beginning of themedication until the death event (Log-Rank test) (Table 5).

In addition, in the group treated with the lowest dose of 30 mg, theurinary frequency event rate as an adverse experience was lower (Table6), and the discontinued rate due to adverse experiences was lower(Table 7), as compared with the data of the groups treated with higherdoses. As a result, it is apparent that the compound of the presentinvention exhibits excellent therapeutic effects on severe heart failureby controlling a dose thereof less than 0.6 mg per 1 kg of body weightper day.

TABLE 1 Study synopsis Name of Product:5-Hydroxy-7-chloro-[2-methyl-4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (A) Study Title: Multicenter,Randomized, Double-Blind, Placebo-Controlled, Study of (A) to Evaluatethe Effects of (A) on the Acute and Chronic Outcomes of Patients withWorsening Congestive Heart Failure Clinical Phase: IIB TreatmentIndication: Patients with Worsening Congestive Heart FailureObjective(s): To assess the efficacy of three doses of (A) or placebo inconjunction with optimal current therapy (as determined by theInvestigator) with up to 10 days of acute inpatient study drug dosing,followed by 7 weeks of outpatient dosing. Study Design: Multicenter,randomized, double-blind, placebo-controlled, parallel groups The studyconsisted of a Screening Day, up to a 10-day inpatient period followedby a 7-week outpatient period. Patients returned for outpatientassessments on Outpatient Weeks 1, 3, 5, and 7. A follow-up telephonecontact occurred 7 days after the last dose of study drug. Four groupsof about 80 patients were randomized to receive once daily for up to 59days: 1) placebo, 2) 30 mg of (A), 3) 60 mg of (A), or 4) 90 mg of (A)All patients continued to receive conventional therapy which may includediuretics, digoxin, ACE inhibitors, hydralazine, nitrates, beta blockersSubject Population: Patients hospitalized for worsening heart failureNYHA class III-IV Male and Female ≧18 years of age Test Product, Dose,(A) 30 mg, 60 mg, 90 mg, or placebo oral Mode of tablets Administration:Endpoints: Efficacy: INPATIENT PRIMARY: Body weight changes at 24 hourspost dosing INPATIENT SECONDARY: NYHA classification, dyspnea,orthopnea, body weight at discharge, edema, jugular venous distention,rales, hepatomegaly, urine output, daily serum electrolytes, length ofstay, diuretic usage, patient and physician assessed symptom scoreOUTPATIENT PRIMARY: Worsening of heart failure defined as any of thefollowing: 1. Hospitalization, 2. Unscheduled visit for CHF to anemergency department, outpatient clinic, or observations unit associatedwith need for either increased therapy or new therapy for heart failure,3. Death. Rates of withdrawal due to worsening heart failure, and timeto withdrawal was analyzed. OUTPATIENT SECONDARY: NYHA classification,edema, body weight, jugular venous distention, rales, hepatomegaly,dyspnea, orthopnea, urine output, serum electrolytes, patient andphysician assessed symptom score SAFETY: Adverse events, vital signs,clinical laboratory tests, PT/APTT, 12-lead electrocardiograms, andphysical examinations PK: Plasma (A) and metabolite concentrations

TABLE 2 Total urine output on Day 1 in patients treated with (A) DayPlacebo 30 mg 60 mg 90 mg 1 2296.46 ± 1134.13  4056.16 ± 2310.23**4175.15 ± 2695.44** 4127.27 ± 2050.81** (76) (73) (82) (73) 2 2317.20 ±1168.09  3905.61 ± 1942.03** 3699.26 ± 2094.02** 3961.73 ± 2129.11**(61) (67) (74) (64) 3 1164.27 ± 1003.99  3579.04 ± 1867.86** 3420.41 ±1902.77** 4069.32 ± 2306.07** (4B) (52) (54) (50) 6 1896.36 ± 1054.423146.67 ± 1618.09 3684.56 ± 2472.45*  4188.23 ± 2275.15** (22) (33) (32)(30) 7 1941.67 ± 1349.94 2662.81 ± 1507.51 4230.00 ± 1691.43*  3915.12 ±2101.53  (12) (16) (17) (17) 9 1989.17 ± 386.14  2908.00 ± 475.59 3753.18 ± 2415.48  2421.43 ± 1391.12   (6)  (5) (11)  (7) Mean ± SD Thenumber in parentheses indicates the number of patients measured. **p <0.01, *p < 0.05, Significant difference vs. placebo

TABLE 3 Mean change in body weight from baseline in patients treatedwith (A) Time Placebo 30 mg 60 mg 90 mg Day 1 −0.87 ± 1.95 −2.14 ±2.63** −2.10 ± 1.80** −1.90 ± 2.87** (78) (76) (76) (74) Day 2 −1.45 ±2.52 −3.49 ± 3.80** −3.03 ± 2.48  −2.84 ± 3.16** (57) (63) (65) (61) Day3 −2.46 ± 2.42 −4.78 ± 4.14** −3.93 ± 3.33*  −2.65 ± 4.22  (45) (49)(47) (45) Dis- −2.56 ± 3.17 −4.37 ± 4.69** −4.60 ± 4.67** −3.75 ± 4.18 charge (78) (76) (82) (76) Week 1 −1.80 ± 4.53 −2.71 ± 4.93  −2.73 ±5.45  −3.23 ± 4.46  (63) (65) (59) (53) Week 7 −1.24 ± 5.16 −2.12 ±5.16  −2.87 ± 6.67  −2.23 ± 5.19  (59) (54) (54) (53) Last −1.32 ± 4.77−2.42 ± 5.37  −3.60 ± 6.38  −2.39 ± 5.20  Visit (78) (76) (82) (76) Mean± SD The number in parentheses indicates the number of patientsmeasured. **p < 0.01, *p < 0.05, Significant difference vs. placebo

TABLE 4 Serum sodium concentration in patients treated with (A) TimePlacebo 30 mg 60 mg 90 mg Baseline 132.81 ± 2.37 132.13 ± 3.44 130.86 ±4.00 133.07 ± 2.52 (16) (15) (22) (15) Day 1 134.75 ± 4.34 136.00 ± 3.96135.77 ± 6.16 137.13 ± 4.82 (16) (15) (22) (15) Day 2 135.45 ± 5.03135.09 ± 5.07 137.29 ± 3.02 137.00 ± 4.60 (11) (11) (17) (15) Day 3134.78 ± 4.76 135.13 ± 5.38 138.62 ± 4.44 136.45 ± 4.59  (9)  (8) (13)(11) Discharge 133.56 ± 3.10 136.13 ± 4.61  137.18 ± 4.56* 137.13 ± 3.02(16) (15) (22) (15) Week 1 133.77 ± 4.75  138.25 ± 4.22*  136.88 ± 5.82*136.13 ± 3.64 (13) (12) (16)  (8) Week 7 134.67 ± 5.52 137.60 ± 4.65 139.36 ± 4.76* 138.00 ± 5.73  (9) (10) (11)  (6) Last Visit 133.88 ±5.15 137.00 ± 5.04 136.18 ± 5.94 136.60 ± 5.17 (16) (15) (22) (15) Mean± SD The number in parentheses indicates the number of patientsmeasured. **p < 0.01, *p < 0.05, Significant difference vs. placebo

TABLE 5 Mortality of the patients treated with (A) Placebo 30 mg 60 mg90 mg Events (80) (78) (84) (77) Number off Death 7 3 8 2 Event Rate (%)8.7% 3.8% 9.5% 2.5% P-value 0.0326 0.7862 0.1460 The number inparentheses indicated the number of patients randomized in the group.Analysis on “Time to Death (on therapy)” were performed by Log-Ranktest.

TABLE 6 Adverse events observed in patients treated with (A) Placebo 30mg 60 mg 90 mg Adverse Event (79) (78) (84) (76) Urinary Frequency 1 1 34 Event Rate (%) 1.3% 1.3% 3.6% 5.3% The number in parentheses indicatedthe number of patients randomized in the group.

TABLE 7 Discontinued cases due to adverse experiences in patientstreated with (A) Reason of Placebo 30 mg 60 mg 90 mg Discontinuation(80) (78) (84) (77) Adverse Experience 12 14 25 17 Event Rate (%) 15.0%17.9% 29.8% 22.1% The number in parentheses indicated the number ofpatients randomized in the group.

INDUSTRIAL APPLICABILITY

The method for the treatment of severe heart failure of the presentinvention is quite useful in the treatment of severe heart failure, i.e.acute heart failure and chronic heart failure in acute excerbation. Inaddition, the method of the present invention is excellently safe withfew side effects. Thus, the present invention provides a method for thetreatment of severe heart failure by administering to a patient abenzazepine compound (1) or a pharmaceutically acceptable salt thereof,and a pharmaceutical composition containing said benzazepine compound(1) or a pharmaceutically acceptable salt thereof as well as a use ofsaid active compound for manufacturing a medicament suitable for thetreatment of severe heart failure.

1. A method for treating severe heart failure of New York HeartAssociation Class IV, comprising administering to a patient in needthereof a therapeutically effective amount of an active compound,5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine or apharmaceutically acceptable salt thereof in a daily dose of less than0.6 mg/kg.
 2. The method according to claim 1, wherein the daily dose isin the range from 0.1 mg/kg to less than 0.6 mg/kg.
 3. A method fortreating severe heart failure of New York Heart Association Class IV,comprising administering to a patient in need thereof a therapeuticallyeffective amount of an active compound,5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepineor a pharmaceutically acceptable salt thereof in a daily dose of 15 to45 mg.
 4. The method according to claim 3, comprising administering tothe patient the active compound in a daily dosage of 30 mg.